Cross-talk between the Tissue Factor-coagulation factor VIIa complex and the tyrosine kinase receptor EphA2 in cancerReport as inadecuate




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BMC Cancer

, 16:341

Cell and molecular biology

Abstract

BackgroundTissue Factor TF forms a proteolytically active complex together with coagulation factor VIIa FVIIa and functions as the trigger of blood coagulation or alternatively activates cell signaling. We recently described that EphA2 of the Eph tyrosine kinase receptor family is cleaved directly by the TF-FVIIa complex. The aim of the present study was to further characterize the cross-talk between TF-FVIIa and EphA2 using in vitro model systems and human cancer specimens.

MethodsCleavage and phosphorylation of EphA2 was studied by Western blot. Subcellular localization of TF and EphA2 was investigated by a proximity ligation assay and confocal microscopy. Phalloidin staining of the actin cytoskeleton was used to study cell rounding and retraction fiber formation. Expression of TF and EphA2 in human colorectal cancer specimens was examined by immunohistochemistry.

ResultsTF and EphA2 co-localized constitutively in MDA-MB-231 cells, and addition of FVIIa resulted in cleavage of EphA2 by a PAR2-independent mechanism. Overexpression of TF in U251 glioblastoma cells lead to co-localization with EphA2 at the leading edge and FVIIa-dependent cleavage of EphA2. FVIIa potentiated ephrin-A1-induced cell rounding and retraction fiber formation in MDA-MB-231 cells through a RhoA-ROCK-dependent pathway that did not require PAR2-activation. TF and EphA2 were expressed in colorectal cancer specimens, and were significantly correlated.

ConclusionsThese results suggest that TF-FVIIa-EphA2 cross-talk might potentiate ligand-dependent EphA2 signaling in human cancers, and provide initial evidence that it is possible for this interaction to occur in vivo.

KeywordsTissue Factor Coagulation factor EphA2 Colorectal cancer Cell signaling Electronic supplementary materialThe online version of this article doi:10.1186-s12885-016-2375-1 contains supplementary material, which is available to authorized users.

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Author: Oskar Eriksson - Åsa Thulin - Anna Asplund - Geeta Hegde - Sanjay Navani - Agneta Siegbahn

Source: https://link.springer.com/







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